The effect of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal
| Project/Area Number |
16K09803
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Kobe University |
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Principal Investigator |
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| Research Collaborator |
Kannno Ayumi
Asahara Shun-ichiro
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | mTORC1活性 / 膵β細胞量 / mTORC1 / DPP-4阻害薬 / 糖尿病 |
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| Outline of Final Research Achievements |
The preservation of pancreatic βcell mass is an essential factior in the onset and development of type 2 diabetes mellitus.In this study, we aimed at indentification of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal. We administered βTSC2-/-mice to DPP-4 inhibitors, SGLT2 inhibitors to db/db mice. DPP-4 inhibitors prevented decrease in insulin signaling. SGLT2 inhibitors preserved pancreatic beta cell mass more effectively if administartion is earlier.
Maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic beta cell mass. Our data suggest that GCN2 senses amino acid deficiency in beta cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent beta cell failure during the consumption of a high-fat diet. The present results provide an insight into the genetic predisposition to T2DM in non-obese Asian populations, and they may inform a strategy for intervention in those with the risk allele for this SNP.
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| Academic Significance and Societal Importance of the Research Achievements |
DPP-4阻害薬はインスリンシグナルの減弱化の改善を介して膵β細胞保護に寄与すると考えられた。早期SGLT2投与db/dbマウスではAgr2、Tff2、Gkn3遺伝子発現上昇により膵β細胞量保持のlegacy effectに寄与している可能性が考えられた。また、GCN2は高脂肪食負荷による過栄養の際、プロインスリンmRNAの翻訳が亢進すると活性化され、SESN2の発現低下によるmTORC1活性の亢進を介して膵β細胞量維持が破綻する可能性が示唆された。すなわち本研究は、2 型糖尿病候補遺伝子GCN2のSNPを有する患者が過食による膵β細胞不全を未然に防ぎうる手段を講じることに役立つと考えられた。
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Report
(4 results)
Research Products
(14 results)
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[Journal Article] Early administration of dapagliflozin preserves pancreatic β-cell mass through a legacy effect in a mouse model of type 2 diabetes2019
Author(s)
Kanno A, Asahara SI, Kawamura M, Furubayashi A, Tsuchiya S, Suzuki E, Takai T, Koyanagi-Kimura M, Matsuda T, Okada Y, Ogawa W, Kido Y.
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Journal Title
J Diabetes Invest.
Volume: 10
Issue: 3
Pages: 577-590
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Docosahexaenoic acid reduces palmitic acid-induced endoplasmic reticulum stress in pancreatic β cells2018
Author(s)
Suzuki E, Matsuda T, Kawamoto T, Takahashi H, Mieda Y, Matsuura Y, Takai T, Kanno A, Kimura-Koyanagi M, Asahara S.-i, Inoue H, Ogawa W, Kido Y
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Journal Title
Kobe J.Med.Sci.
Volume: 64
NAID
Related Report
Peer Reviewed
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[Journal Article] Casein kinase 2 phosphorylates and stabilizes C/EBPβ in pancreatic β cells.2018
Author(s)
Takai T, Matsuda T, Matsuura Y, Inoue K, Suzuki E, Kanno A, Kimura-Koyanagi M, Asahara SI, Hatano N, Ogawa W, Kido Y.
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Journal Title
Biochem Biophys Res Commun.
Volume: 497
Issue: 1
Pages: 451-456
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.2017
Author(s)
Kawada Y, Asahara SI, Sugiura Y, Sato A, Furubayashi A, Kawamura M, Bartolome A, Terashi-Suzuki E, Takai T, Kanno A, Koyanagi-Kimura M, Matsuda T, Hashimoto N, Kido Y.
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Journal Title
PLoS ONE
Volume: 12
Issue: 9
Pages: e0184435-e0184435
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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